CD73 inhibition overcomes adaptive immune resistance to PARP inhibition in models of prostate cancer
Ping Xie, Renqiang Ma, Minghui Zhang, Jie Fan, Hui Tang, Longzhen Song, Yong Wan, Timothy M. Kuzel, Deyu Fang, Weiguo Cui, Jennifer D. Wu, Sarki A. Abdulkadir, Yi Zhang, Akash Patnaik, Bin Zhang
Ping Xie, Renqiang Ma, Minghui Zhang, Jie Fan, Hui Tang, Longzhen Song, Yong Wan, Timothy M. Kuzel, Deyu Fang, Weiguo Cui, Jennifer D. Wu, Sarki A. Abdulkadir, Yi Zhang, Akash Patnaik, Bin Zhang
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Research Article Immunology Oncology

CD73 inhibition overcomes adaptive immune resistance to PARP inhibition in models of prostate cancer

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) remains a leading cause of cancer-related mortality in men. Although poly(ADP-ribose) polymerase (PARP) inhibitors are approved for mCRPC patients with homologous recombination repair (HRR) deficiencies, clinical trials combining olaparib with PD-1/PD-L1 inhibitors showed limited efficacy in unselected populations. To investigate the immunomodulatory effects of PARP inhibitors in an unbiased manner, we performed bulk RNA-seq on HRR-proficient MycCaP cells treated with the PARP inhibitor olaparib versus vehicle control. Transcriptomic analysis revealed robust upregulation of CD73 (NT5E), an ectoenzyme and emerging immune checkpoint that generates extracellular adenosine, suggesting an adaptive mechanism that undermines olaparib efficacy and promotes immunosuppression. CD73 induction by olaparib was validated in human and mouse prostate cancer cell lines, with more pronounced effects in HRR-compromised PTEN-KO cells. Mechanistically, olaparib-driven CD73 expression was mediated through DNA damage–activated ATR/CHEK1/IRF1 and TGF-β1/AKT signaling pathways. In parallel, olaparib enhanced tumor immunogenicity by activating type I IFN signaling and antigen presentation machinery. In vivo, combining olaparib with CD73 blockade significantly delayed tumor growth, improved T cell infiltration, and augmented CD8+ T cell effector function across HRR-proficient and PTEN-KO prostate cancer models. These findings identify olaparib-induced CD73 upregulation as an adaptive resistance mechanism and support olaparib plus CD73 blockade as a promising therapeutic strategy for advanced prostate cancer, irrespective of HRR status.

Authors

Ping Xie, Renqiang Ma, Minghui Zhang, Jie Fan, Hui Tang, Longzhen Song, Yong Wan, Timothy M. Kuzel, Deyu Fang, Weiguo Cui, Jennifer D. Wu, Sarki A. Abdulkadir, Yi Zhang, Akash Patnaik, Bin Zhang

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Figure 5

Combination therapy enhances antitumor CD8+ T cell function and directs spatially immunocompetent interactions among orthotopic prostate tumors.

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Combination therapy enhances antitumor CD8+ T cell function and directs ...
(A) Schematic of the orthotopic MycCaP prostate tumor model and treatment groups, including vehicle control, olaparib monotherapy, α-CD73 monotherapy, and combined olaparib plus α-CD73 (n = 5–7). The tumor weight analyzed at the end of the experiment. (B) Flow cytometry analysis of surface CD73 expression on EpCAM+ tumor cells from treated mice (n = 5–7). (C) Flow cytometry profiling of tumor-infiltrating CD8+ T cells, including total CD8+ T cell infiltration, IFN-γ and TNF-α expression, and proportions of exhausted-like CD8+ T cells (Tex; PD1+ and CD39+) (n = 5–7). (D) Representative mIHC analysis of EpCAM, CD8, IFN-γ, MHC-I (H2Kq), and CD73 staining in orthotopic MycCaP tumors. White arrow, CD8+ IFN-γ– cells; white arrowhead, CD8+ IFN-γ+ cells; red arrow, EpCAM+ CD73–/lo cells; red arrowhead, EpCAM+ CD73+ cells. Scale bar: 100 μm. (E) Quantification of CD8+ T cell density in tumor tissue by mIHC (n = 5). (F) Quantification of intratumoral IFN-γ+ CD8+ T cells density (n = 5). (G) Spatial analysis of the distance between intratumoral CD8+ T cells and EpCAM+ tumor cells stratified by positive or low/negative CD73 expression (n = 5). (H) Quantification of CD8+ T cells located within 20 μm of EpCAM+ tumor cells categorized by positive or low/negative MHC-I (H2Kq) expression (n = 5). Data were analyzed by 2-way ANOVA (A–H) or unpaired 2-tailed Student’s t test (G and H). Data plotted are mean ± SEM from biological replicates. *P < 0.05, **P < 0.01, ***P < 0.001.